Irreversible non-steroidal antagonist compound and its use in the treatment of prostate cancer

ABSTRACT

The present invention relates to an antiandrogen compound and a method of treating prostate cancer in a patient utilizing the compound. The present invention also relates to a pharmaceutical composition which includes the compound.

[0001] The present application claims the benefit of U.S. ProvisionalPatent Application Serial No. 60/031,861, filed Nov. 27, 1996.

FIELD OF THE INVENTION

[0002] The present invention relates to non-steroidal antagonistcompounds and their use in treatment of prostate cancer. Moreparticularly, the present invention relates to an irreversiblenon-steroidal antiandrogen and its use in treating prostate cancer.

BACKGROUND OF THE INVENTION

[0003] Prostate cancer is the most common cancer in men with anestimated 244,000 cases in 1995 in the United States. It is the secondleading cause among men who die from neoplasia with an estimated 44,000deaths per year. Prompt detection and treatment is needed to limitmortality caused by prostate cancer.

[0004] As described in W. J. Catalona, “Management of Cancer of theProstate,” New Engl. J. Med. 331(15):996-1004 (1994) (which is herebyincorporated by reference), the management of prostate cancer can beachieved by watchful waiting, curative treatment, and palliation. Formen with a life expectancy of less than 10 years, watchful waiting isappropriate where low-grade, low-stage prostate cancer is discovered atthe time of a partial prostatectomy for benign hyperplasia. Such cancersrarely progress during the first five years after detection. On theother hand, for younger men, curative treatment is often moreappropriate.

[0005] Where prostate cancer is localized and the patient's lifeexpectancy is 10 years or more, radical prostatectomy offers the bestchance for eradication of the disease. Historically, the drawback ofthis procedure is that most cancers had spread beyond the bounds of theoperation by the time they were detected. However, the use ofprostate-specific antigen testing has permitted early detection ofprostate cancer. As a result, surgery is less expensive with fewercomplications. Patients with bulky, high-grade tumors are less likely tobe successfully treated by radical prostatectomy.

[0006] After surgery, if there are detectable serum prostate-specificantigen concentrations, persistent cancer is indicated. In many cases,prostate-specific antigen concentrations can be reduced by radiationtreatment. However, this concentration often increases again within twoyears.

[0007] Radiation therapy has also been widely used as an alternative toradical prostatectomy. Patients generally treated by radiation therapyare those who are older and less healthy and those with higher-grade,more clinically advanced tumors. Particularly preferred procedures areexternal-beam therapy which involves three dimensional, conformalradiation therapy where the field of radiation is designed to conform tothe volume of tissue treated, and interstitial-radiation therapy whereseeds of radioactive compounds are implanted using ultrasound guidance.

[0008] Cytotoxic chemotherapy is largely ineffective in treatingprostate cancer. Its toxicity makes such therapy unsuitable for elderlypatients. In addition, prostate cancer is relatively resistant tocytotoxic agents.

[0009] Androgens are known to stimulate growth of the prostate and otherperipheral tissues, including primary or metastatic prostate tumorcells. Testosterone (“T”) is the principal androgen secreted by thetestes and is the primary circulating androgen found in the plasma ofmales. The testes produce 95% of circulating plasma T, while theremaining 5% is derived from the adrenals. In many target tissues, T isconverted by the enzyme 5α-reductase to the more potent androgendihydrotestosterone (“DHT”). T and DHT then compete for binding to theandrogen receptor (“AR”) to exert their influence on cell function. DHThas a four- to five-fold higher AR binding affinity than does T and thusserves as the intracellular mediator for most actions of the hormone.However, both androgens contribute to the overall androgenic effect. Thehigh response rate (i.e., 60 to 80%) to first line hormonal therapy andthe presence of AR in both primary and metastatic prostate tumor cellssupport the idea that the AR is an important mediator of prostate cancerdevelopment and growth. Denis et al., “Prostatic Cancer: An Overview,”Acta. Oncol., 29:665-677 (1990); McConnell, “Physiologic Basis ofEndocrine Therapy for Prostatic Cancer,” Urol. Clin. N. Am., 18(1):1-13(1991) (which are hereby incorporated by reference)

[0010] Because prostatic carcinomas are androgen dependent, varioustreatment strategies focus on negating the role of androgens (i.e.,testosterone and dihydrotestosterone) in prostate tumor growth. Labrie,“Endocrine Therapy for Prostate Cancer,” Endocrinol. Metab. Clin. N.Am., 20(4):845-872 (1991); Soloway, et al., “Antiandrogenic Agents asMonotherapy in Advanced Prostatic,” Cancer, 71(Suppl. 3): 1083-1088(1993) (which are hereby incorporated by reference). These treatmentstrategies include use of luteinizing hormone-releasing hormone (“LHRH”)to suppress testicular androgen production or orchiectomy (surgicalcastration) to eliminate androgen production.

[0011] In recent years, antiandrogens have been widely used for thetreatment of prostate cancer. The biologic activity of androgens ismediated through the formation of a non-covalent androgenreceptor-steroid complex. Antiandrogens inhibit formation if thiscomplex and, thus, negate the role of endogenous steroids inandrogen-dependent growth of the prostate.

[0012] Antiandrogens can be divided into two groups: steroidal andnon-steroidal. There are several non-steroidal antiandrogens such asFlutamide (Eulexin), Nilutamide (Anandrone), and Casodex. All of thembind reversibly to the AR. Accordingly, these antiandrogens can bedisplaced by an endogenous ligand such as dihydrotestosterone.Therefore, these antiandrogens have not been successful in the treatmentof prostate cancer. Earlier reports suggested that dihydrotestosteronebromoacetate (DHT-BA) binds irreversibly to the AR. However, recentevidence showed that DHT-BA binds aldehyde dehydrogenase, and not theAR. McCammon et al., “An Androgenic Affinity Ligand Covalently Binds toCytosolic Aldehyde Dehydrogenase from Human Genital Skin Fibroplast,”Mol. Cell. Endocrinology, 91:177-183 (1993), which is herebyincorporated by reference. Therefore, DHT-BA is not suitable fortreating prostate cancer.

[0013] The present invention is directed to overcoming thesedeficiencies.

SUMMARY OF THE INVENTION

[0014] The present invention relates to a method of treating prostatecancer in a patient which includes administering to the patient aneffective amount of a compound which binds irreversibly to the androgenreceptor of the patient.

[0015] Another aspect of the present invention relates to a method oftreating prostate cancer in a patient which includes administering tothe patient an effective amount of a compound having the formula:

[0016] where R₁, R₂ and R₃, are the same or different and are ahydrogen, a nitro, a cyano, a carbamoyl, a halogen, a perfluoroalkyl, ahaloalkylamido, an isothiocyanate, an azide, a diazocarbonyl, asubstituted oxirane, or a β-chloroethylamine

[0017] R₄ is a hydrogen, an alkyl, or is joined to R₅;

[0018] R₅ is a hydrogen, a hydroxy, an alkoxy, an acyloxy, an amino, analkylamino, a halogen, or is joined to R₄;

[0019] R₆ is a hydrogen, an alkyl, or a halogenoalkyl;

[0020] A₁ and A₂ are the same or different, and each is a direct link oran alkylene;

[0021] X₁ is a halogen, an oxygen, a sulfur, a sulphinyl, a sulphonyl,an amino, or an alkylimino, or alkylene;

[0022] R₇ is a hydrogen, a halogen, an alkoxy, a haloalkoxy, an acyloxy,a haloacyloxy, an aryloxy, a thioalkyl, a thioraryl, a sulphinyl, ahaloalkyl sulphinyl, a sulphonyl, a haloalkylsulphonyl, an amino, analkylimino, an alkylamido group, a haloalkylamido group, anisothiocyanate, an azide, a diazocarbonyl, a sustituted oxirane, aβ-chloroethylamine, or a phenyl optionally substituted with halogen, anitro group, an alkyl, a haloalkyl, a cyano, a hydroxyl, a carboxylicgroup, an amino, an alkylamino, an alkylamido group, a haloalkylamidogroup, an isothiocyanate, an azide, a diazocarbonyl, a substitutedoxirane, or a β-chloroethylamine. The compound binds irreversibly to anandrogen receptor of the patient.

[0023] The present invention also relates to the compound and to apharmaceutical composition which includes the compound and apharmaceutically suitable carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

[0024]FIG. 1 shows the chemical structure and AR binding affinities ofcompounds of the present invention.

[0025]FIG. 2 shows the binding affinities of compounds of the presentinvention.

[0026]FIG. 3 shows the irreversible binding of compounds of the presentinvention to AR.

DETAILED DESCRIPTION OF THE INVENTION

[0027] The present invention relates to a method of treating prostatecancer in a patient which includes administering to the patient aneffective amount of a compound which binds irreversibly to the androgenreceptor of the patient.

[0028] The present invention relates to a method of treating prostatecancer in a patient which includes administering to the patient aneffective amount of a compound having the formula:

[0029] where R₁, R₂, and R₃ are the same or different and are ahydrogen, a nitro, a cyano, a carbamoyl, a halogen, a perfluoroalkyl, ahaloalkylamido, an isothiocyanate, an azide, a diazocarbonyl, asubstituted oxirane, or a β-chloroethylamine;

[0030] R₄ is a hydrogen, an alkyl, or is joined to R₅;

[0031] R₅ is a hydrogen, a hydroxy, an alkoxy, an acyloxy, an amino, analkylamino, a halogen, or is joined to R₄;

[0032] R₆ is a hydrogen, an alkyl, or a halogenoalkyl;

[0033] A₁ and A₂ is the same or different, each is direct link or analkylene;

[0034] X₁ is a halogen, an oxygen, a sulfur, a sulphinyl, a sulphonyl,an amino, an alkylimino, or an alkylene;

[0035] R₇ is a hydrogen, a halogen, an alkoxy, a haloalkoxy, a acyloxy,a haloacyloxy, an aryloxy, a thioalkyl, a thioraryl, a sulphinyl, ahaloalkyl sulphinyl, a sulphonyl, a haloalkylsulphonyl, an amino, analkylimino, an alkylamido group, a haloalkylamido group, anisothiocyanate, an azide, a diazocarbonyl, a substituted oxirane, aβ-chloroethylamine, or a phenyl optionally substituted with a halogen, anitro group, an alkyl, a haloalkyl, a cyano, a hydroxyl, a carboxylicgroup, an amino, an alkylamino, an alkylamido group, a haloalkylamidogroup, an isothiocyanate, an azide, a diazocarbonyl, a substitutedoxirane, or a β-chloroethylamine. The compound binds irreversibly to anandrogen receptor of the patient.

[0036] The subject invention is best understood through a discussion ofreceptors and signal transduction pathways. Cells in higher animalsnormally communicate by means of hundreds of kinds of extracellularsignaling molecules, including proteins, small peptides, amino acids,nucleotides, steroids, retinoids, fatty acid derivatives, and evendissolved gases such as nitric oxide and carbon monoxide. Thesesignaling molecules relay a “signal” to another cell (a “target cell”),generally affecting a cellular function. As used herein, receptors forextracellular signaling molecules are collectively referred to as “cellsignaling receptors”.

[0037] Many cell signaling receptors are transmembrane proteins on acell surface; when they bind an extracellular signaling molecule (aligand), they become activated so as to generate a cascade ofintracellular signals that alter the behavior of the cell. In contrast,in some cases, the receptors are inside the cell and the signalingligand has to enter the cell to activate them; these signaling moleculestherefore must be sufficiently small and hydrophobic to diffuse acrossthe plasma membrane of the cell. As used herein, these receptors arecollectively referred to as “intracellular cell signaling receptors”.

[0038] Steroid hormones are one example of small hydrophobic moleculesthat diffuse directly across the plasma membrane of target cells andbind to intracellular cell signaling receptors. These receptors arestructurally related and constitute the intracellular receptorsuperfamily (or steroid-hormone receptor superfamily). Steroid hormonereceptors include progesterone receptors, estrogen receptors, androgenreceptors, glucocorticoid receptors, and mineralocorticoid receptors.The present invention is particularly directed to androgen receptors.

[0039] In addition to ligand binding to the receptors, the receptors canbe blocked to prevent ligand binding. When a substance binds to areceptor, the three-dimensional structure of the substance fits into aspace created by the three-dimensional structure of the receptor in aball and socket configuration. The better the ball fits into the socket,the more tightly it is held. This phenomenon is called affinity. If theaffinity of a substance is greater than the original hormone, it willcompete with the hormone and bind the binding site more frequently. Oncebound, signals may be sent through the receptor into the cells, causingthe cell to respond in some fashion. This is called activation. Onactivation, the activated receptor then directly regulates thetranscription of specific genes. But the substance and the receptor musthave certain attributes, other than affinity, in order to activate thecell. Chemical bonds between atoms of the substance and the atoms of thereceptors must form. In some cases, this leads to a slight change in theconfiguration of the receptor which is enough to begin the activationprocess (called signal transduction). As a result, substances can bemade which bind receptors and activate them (called receptor agonists)or inactivate them (called receptor antagonists).

[0040] The present invention is directed to compounds which areantagonists compounds, and are, therefore, useful in blocking steroidalhormone receptors. Preferably, the antagonist compound of the presentinvention is an antiandrogen which binds the androgen receptor. Moreparticularly, the present invention is a compound which bindsirreversibly to the androgen receptor to inhibit formation of a androgenreceptor-steroid complex to prevent prostate cancer. In particular, thecompound of the present invention contains an active (i.e.electrophilic) functional group (or affinity label) that allowsalkylation of the androgen receptor (i.e. allows covalent bond formationbetween the receptor and the functional group). Thus, the compound bindsirreversibly to the receptor and, accordingly, cannot be displaced bythe steroid, because of the chemical strength of the covalentinteraction, the receptor is rendered permanently nonfunctional. Inparticular, the compound of the present invention irreversibly binds tothe androgen receptor preventing displacement of the compound by theendrogenous ligands dihydrotestosterone and testosterone.

[0041] The compounds which are useful in binding irreversibly to theandrogen receptor are acylanilides have the formula:

[0042] wherein R₁, R₂, and R₃ are the same or different, and each is ahydrogen, a nitro, a cyano, a carbamoyl, a halogen, a perfluoroalkyl, ahaloalkylamido, an isothiocyanate, an azide, a diazocarbonyl, asubstituted oxirane, a β-chloroethylamine, or other defined andexemplified substituents;

[0043] R₄ is a hydrogen, an alkyl, or is joined to R₅;

[0044] R₅ is a hydrogen, a hydroxy, an alkoxy, an acyloxy, an amino, analkylamino, a halogen, or is joined to R₄;

[0045] R₆ is a hydrogen, an alkyl, or a halogenoalkyl;

[0046] A₁ and A₂ is the same or different, each is direct link oralkylene;

[0047] X₁ is a halogen, an oxygen, a sulfur, a sulphinyl, a sulphonyl,an amino, an alkylimino, or an alkylene; and

[0048] R₇ is a hydrogen, a halogen, an alkoxy, a haloalkoxy, an acyloxy,a haloacyloxy, an aryloxy, a thioalkyl, a thioraryl, a sulphinyl, ahaloalkyl sulphinyl, a sulphonyl, a haloalkylsulphonyl, an amino, analkylimino, an alkylamido group, a haloalkylamido group, anisothiocyanate, an azide, a diazocarbonyl, a substituted oxirane, aβ-chloroethylamine, or a phenyl optionally substituted with a halogen, anitro group, an alkyl, a haloalkyl, a cyano, a hydroxyl, a carboxylicgroup, an amino, an alkylamino, an alkylamido group, a haloalkylamidogroup, an isothiocyanate, an azide, a diazocarbonyl, a substitutedoxirane, a β-chloroethylamine, or other defined and exemplifiedsubstituents.

[0049] Although the compounds of the present invention have affinitylabels at either the R₇ or R₂ position, compounds having the affinitylabel at other positions may be utilized.

[0050] In particular, the compounds shown below in Table 1 are useful ina method of treating prostate cancer in a patient where the compoundbinds irreversibly to the androgen receptor of the patient. TABLE 1R-isomers S-isomers Compound Compound No. Compound No.

R-1  S-1 

R-2  S-2 

R-3  S-3 

R-4  S-4 

R-5  S-5 

R-6  S-6 

R-7  S-7 

R-8  S-8 

R-9  S-9 

R-10 S-10

R-11 S-11

R-12 S-12

R-13 S-13

R-14 S-14

R-15 S-15

R-16 S-16

R-17 S-17

R-18 S-18

R-19 S-19

R-20 S-20

[0051] where Me is a methyl group.

[0052] Especially desirable compounds useful as antagonist compounds fortreating prostate cancer have the formula:

[0053] Where Z is NCS or CN, R is F, NH₂, NCS, N₃, or NHCOCH₂Y, X is Sor SO₂, and Y is a halogen, preferably Cl or Br.

[0054] Particularly desirable compounds of the invention are where Z isCN, X is S, and R is either NCS or NHCOCH₂, Cl, or where Z is CN, X isSO₂, and R is NCS, or where Z is NCS, X is SO₂, and R is F.

[0055] As discussed above, the high response rate to first line hormonaltherapy and the presence of AR in both primary and metastatic prostatetumor cells support the idea that AR is an important mediator ofprostate cancer development and growth. Accordingly, by irreversiblybinding the compound of the present invention to the AR of a patient,therey blocking formation of the AR-hormone complex, the growth anddevelopment of prostate cancer is slowed or eliminated. The presentinvention, therefore, is directed to a method of treating prostatecancer in a patient where the compound of the present invention isadministered to the patient in an effective amount, where the compoundbinds irreversibly to the androgen receptor of the patient.

[0056] The compounds herein may be made up in any suitable formappropriate for the desired use; e.g., oral, parenteral (for example,subcutaneously, intravenously, interamuscularly, intraperitoneally, byintranasal instillation, or by application to mucous membranes, such asthat of the nose, throat, and bronchial tubes, or by instillation intohollow organ walls or newly vascularized blood vessels) or topicaladministration. Suitable dosage forms for oral use include tablets,dispersible powders, granules, capsules, suspensions, syrups, andelixirs. The compounds may be administered alone or with suitablepharmaceutical diluents or carriers. Inert diluents and carriers fortablets include, for example, calcium carbonate, sodium carbonate,lactose, and talc. Tablets may also contain granulating anddisintegrating agents such as starch and alginic acid, binding agentssuch as starch, gelatin, and acacia, and lubricating agents such asmagnesium stearate, stearic acid, and talc. Tablets may be uncoated ormay be coated by known techniques to delay disintegration andabsorption. Inert diluents and carriers which may be used in capsulesinclude, for example, calcium carbonate, calcium phosphate, and kaolin.Suspensions, syrups, and elixirs may contain conventional excipients,for example, methyl cellulose, tragacanth, sodium alginate; wettingagents, such as lecithin and polyoxyethylene stearate; andpreservatives, e.g., ethyl-p-hydroxybenzoate.

[0057] Dosage forms suitable for parenteral administration includesolutions, suspensions, dispersions, emulsions, and the like. They mayalso be manufactured in the form of sterile solid compositions which canbe dissolved or suspended in sterile injectable medium immediatelybefore use. They may contain suspending or dispersing agents known inthe art.

[0058] It will be appreciated that the actual preferred amount of thecompound to be administered according to the present invention will varyaccording to the particular compound, the particular compositionformulated, and the mode of administration. Many factors that may modifythe action of the inhibitor can be taken into account by those skilledin the art; e.g., body weight, diet, time of administration, route ofadministration, rate of excretion, condition of the subject, drugcombinations, and reaction sensitivities and severities. Administrationcan be carried out continuously or periodically within the maximumtolerated dose. Optimal administration rates for a given set ofconditions can be ascertained by those skilled in the art usingconventional dosage administration tests.

[0059] The acylanilides of the invention may be manufactured by anychemical process known to be suitable for the manufacture ofchemically-analogous compounds. Examples of suitable chemical processesfor manufacturing acylanilides are shown in U.S. Pat. No. 4,636,505 toTucker, which is hereby incorporated by reference. One preferred processfor the manufacture of an acylanilide of the invention comprises thereaction of an amine of the formula:

[0060] wherein R₁, R₂, R₃, are the same or different, and each is ahydrogen, a nitro, a cyano, a carbamoyl, a halogen, a perfluoroalkyl, ahaloalkylamido, an isothiocyanate, an azide, a diazocarbonyl, asubstituted oxirane, a β-chloroethylamine, or other defined andexemplifies substituents and R₄ is a hydrogen, or an alkyl, with an acidof the formula:

[0061]  HO₂C-CR₅R₆-A₁-X₁-A₂-R₇

[0062]

[0063] wherein R₅ is a hydrogen, a hydroxy, an alkoxy, an acyloxy, anamino, an alkylamino, a halogen; R₆ is a hydrogen, an alkyl, or ahalogenoalkyl; A₁ and A₂ is the same or different, each is direct linkor alkylene; X₁ is a halogen, an oxygen, a sulfur, a sulphinyl, asulphonyl, an amino, an alkylimino, or an alkylene; and R₇ is ahydrogen, a halogen, an alkoxy, a haloalkoxy, an acyloxy, a haloacyloxy,an aryloxy, a thioalkyl, a thioraryl, a sulphinyl, a haloalkylsulphinyl, a sulphonyl, a haloalkylsulphonyl, an amino, an alkylimino,an alkylamido group, a haloalkylamido group, an isothiocyanate, anazide, a diazocarbonyl, a substituted oxirane, a β-chloroethylamine, ora phenyl optionally substituted with a halogen, a nitro group, an alkyl,a haloalkyl, a cyano, a hydroxyl, a carboxylic group, an amino, analkylamino, an alkylamido group, a haloalkylamido group, anisothiocyanate, an azide, a diazocarbonyl, a substituted oxirane, aβ-chloroethylamine, or with a reactive derivative of said acid.

[0064] A suitable reactive derivative of an acid is, for example, anacid anhydride, or an acyl halide, for example an acyl chloride, or alower alkyl ester of said acid, for example the methyl or ethyl ester.Preferably the reaction is carried out in N,N-dimethylacetamide solutionusing an acyl chloride (prepared from the acid and thionyl chloride) asreactant.

[0065] A second preferred process for the manufacture of an acylanilideof the invention wherein R₅ is hydroxy and X₁ is sulphur or alkyliminocomprises the reaction of an epoxide of the formula:

[0066] wherein R₁, R₂, R₃ and R₄ have the meanings stated above andwherein Z₁ has the formula:

[0067] wherein R₆ has the meaning stated above, wherein Z₂ is adisplaceable group and wherein R₁₁ is such that -CHR₁₁-is-A₁ as statedabove, with a thiol or amine of the formula:

R₇-A₂-SH or R₇-A₂-NHR₁₀

[0068] wherein R₇ and A₂ have the meanings stated above and R₁₀ is analkyl.

[0069] A suitable value for Z₂ is, for example, a halogeno orsulphonyloxy group, for example the chloro, bromo, iodo,methanesulphonyloxy, or p-toluenesulphonyloxy group. The above-mentionedreaction is preferably carried out in an inert diluent or solvent, forexample tetrahydrofuran, and in the presence of a base, for examplesodium hydride.

[0070] The epoxide used as starting material may be obtained by theepoxidation, for example with a per-acid, of the correspondingunsaturated acylanilide.

[0071] A third preferred process for the manufacture of an acylanilideof the invention wherein R₅ is hydroxy comprises the reaction of acompound of the formula:

[0072] wherein R₁, R₂, R₃ and R₄ and R₆ have the meanings stated above,with an organometallic compound of the formula:

R₇-A₂-X₁-A₁-M

[0073] wherein A₁, A₂, R₇, and X₁ have the meanings stated above and Mis a metal radical, for example the lithium radical.

[0074] The last-mentioned reaction is preferably carried out in an inertsolvent, for example diethyl ether or tetrahydrofuran, at a lowtemperature, for example at between −60° C. and −100° C.

[0075] An acylanilide of the invention wherein R₄ and R₅ are joinedtogether to form a carbonyloxy group, that is, an oxazolidinedione, maybe prepared by the reaction of an isocyanate of the formula:

[0076] wherein R₁, R₂, and R₃ have the meanings stated above, with anester of the formula:

[0077] wherein R₆, R₇, X₁, A₁ and A₂ have the meanings stated above, andwherein R is alkyl of up to 6 carbon atoms, for example methyl or ethyl.This reaction is preferably carried out in an organic solvent, forexample diethyl ether, at laboratory temperature.

[0078] An acylanilide of the invention wherein R₅ is hydroxy may beprepared by the hydrolysis of the corresponding acylanilide wherein R₅is acyloxy, and an acylanilide of the invention wherein R₅ is hydroxyand R₄ is hydrogen may be prepared by the hydrolysis of thecorresponding oxazolidinedione, which may be prepared as described inthe preceding paragraph.

[0079] An acylanilide of the invention wherein R₄ is alkyl may beprepared by the alkylation of the corresponding acylanilide wherein R₄is hydrogen.

[0080] An acylanilide of the invention wherein R₅ is acyloxy may beprepared by the acylation of the corresponding acylanilide wherein R₅ ishydroxy.

[0081] An oxazolidinedione of the invention, wherein R₄ and R₅ arejoined together to form a carbonyloxy group, may be prepared by thereaction of the corresponding acylanilide wherein R₄ is hydrogen and R₅is hydroxy with phosgene (COCl₂).

[0082] An acylanilide of the invention wherein X₁ or X₂ is sulphinyl orsulphonyl or wherein one or more of R₁, R₂, and a substituent in thephenyl or heterocyclic group R₇ is alkylsulphinyl,perfluoroalkylsulphinyl or phenylsulphinyl, or is alkylsulphonyl,perfluoroalkylsulphonyl or phenylsulphonyl, may be prepared by theoxidation of the corresponding acylanilide wherein X₁ or X₂ is sulphuror wherein one or more of R₁, R₂ and a substituent in the phenyl orheterocyclic group R₇, is alkylthio, perfluoroalkylthio or phenylthio.The oxidizing agent and conditions used will determine whether asulphinyl or a sulphonyl compound is obtained. Thus, oxidation withsodium metaperiodate in methanol solution at or below laboratorytemperature will generally convert a thiocompound into the correspondingsulphinyl compound; and oxidation with a per-acid, for examplem-chloroperbenzoic acid, in methylene chloride solution at or abovelaboratory temperature will generally convert a thio compound into thecorresponding sulphonyl compound.

[0083] A racemic acylanilide of the invention wherein R₅ is hydroxy maybe separated into its optical isomers by forming an ester of the hydroxygroup R₅ with an optically-active acid, for example (−)-camphanic acid,separating the diastereoisomeric esters thus obtained, by fractionalcrystallisation or, preferably, by flash-chromatography, and thenhydrolyzing each separate ester to the alcohol. Alternatively, anoptically active acylanilide of the invention may be obtained by usingany of the processes described above with an optically active startingmaterial.

[0084] As stated above, an acylanilide of the invention possessesantiandrogenic properties. An acylanilide of the invention may,therefore, be used in the treatment of malignant or benign prostaticdisease or of other androgen dependent disease conditions, such as acne,hirsutism or seborrhoea, in a patient, such as warm-blooded vertebrates,including man. It may also be used to improve ovulation in a domesticanimal. In addition, the compounds may be radiolabeled. Suchradiolabeled ligands are useful for the detection of prostate cancer bythe imaging and staging of localized and metastatic prostate tumors.

[0085] In another aspect of the present invention, compounds which areagonists to the androgen receptor bind to and activate the androgenreceptor. Acylanides having the formula:

[0086] wherein R₁, R₂ and R₃, are the same or different and are ahydrogen, a nitro, a cyano, a carbamoyl, a halogen, a perfluoroalkyl, ahaloalkylamido, an isothiocyanate, an azide, a diazocarbonyl, asubstituted oxirane, or a β-chloroethylamine;

[0087] R₄ is a hydrogen, an alkyl, or is joined to R₅;

[0088] R₅ is a hydrogen, a hydroxy, an alkoxy, an acyloxy, an amino, analkylamino, a halogen, or is joined to R₄;

[0089] R₆ is a hydrogen, an alkyl, or a halogenoalkyl;

[0090] A₁ and A₂ is the same or different, each is direct link oralkylene;

[0091] X₁ is a halogen, an oxygen, a sulfur, a sulphinyl, a sulphonyl,an amino, an alkylimino, or an alkylene; and

[0092] R₇ is a hydrogen, a halogen, an alkoxy, a haloalkoxy, an acyloxy,a haloacyloxy, an aryloxy, a thioalkyl, a thioraryl, a sulphinyl, ahaloalkyl sulphinyl, a sulphonyl, a haloalkylsulphonyl, an amino, analkylimino, an alkylamido group, a haloalkylamido group, anisothiocyanate, an azide, a diazocarbonyl, a substituted oxirane, aβ-chloroethylamine, or a phenyl optionally substituted with a halogen, anitro group, an alkyl, a haloalkyl, a cyano, a hydroxyl, a carboxylicgroup, an amino, an alkylamino, an alkylamido group, a haloalkylamidogroup, an isothiocyanate, an azide, a diazocarbonyl, a substitutedoxirane, or a β-chloroethylamine are useful as agonists of the androgenreceptor and are, therefore, useful for a variety of therapeuticsituations including male contraception and hormone replacement therapy.Compounds shown below in Table 2 are especially desirable agonists ofthe androgen receptor. TABLE 2 R-isomers S-isomers Compound Compound No.Compound No.

R-1 S-1

R-2 S-2

R-3 S-3

R-4 S-4

R-5 S-5

R-6 S-6

EXAMPLES Example 1

[0093] (R)-and (S)-enantiomeric analogs of Casodex bearing affinitylabels such as isothiocyanates, chloroacetamides, bromoacetamides, orazides were synthesized. The synthesized compounds according to theformula:

[0094] are shown in Table 3 below: TABLE 3 Substituents R-isomersS-isomer R X No. K_(i), nM No. K_(i), nM 4-NH₂ S R-1 70 S-1 830 3-NH₂ SR-2 40 S-2 2300 4-NCS S R-3 400 S-3 ≈4000 4-NCS SO₂ R-4 30 4-N₃ S R-511.5 4-NHCOCH₂Cl S R-6 1.6 4-NHCOCH₂Br S R-7 200 4-NHCOCH₂Br SO₂ R-8 1003-NCS S R-9 380 S-9 2700 3-NCS SO₂ R-10 90 3-NHCOCH₂Cl S R-11 11003-NHCOCH₂Br S R-12 250

[0095] Analogs bearing an amine affinity labels were produced by thefollowing procedure. (S)- or (R)-proline was used as the chiral matrixfor syntheses of (R)- and (S)-anilines (R-1, R-2, S-1, and S-2 in Table3) in Scheme 1 (shown below) as the starting materials for preparationof the affinity labels. This scheme is similar to the general syntheticroute reported by Tucker and Chesterson for (S)-Casodex, in Tucker etal., “Resolution of the Non-steroidal Antiandrogen4′-Cyano-3-[(4-flurophenyl)sulfonyl)]-2-hydroxy-2-methyl-3′-(trifluromethyl)-propioanilideand Determination of the Absolute Configuration of the ActiveEnantiomer,” J. Med. Chem., 31:885-887 (1988); Tucker et al.,“Nonsteroidal Antiandrogens. Synthesis and Structure-ActivityRelationships of 3-Substituted Derivatives of 2-Hydroxypropionanilides,”J. Med. Chem., 31(5)954-959 (1988).

[0096] Analogs bearing an isothiocyanate affinity label were produced bythe procedure shown in Scheme 2. Synthesis of the isothiocyanates (R-3and R-9) was carried out with excellent yields (87-99%) according to theprocedure of Leclerc et al., “Agens Alpha-adrenérgiques Alcoylants, 2,”Eur. J. Med. Chem., 18(4) 379-383 (1983), (shown in Scheme 2) in atwo-phase aqueous-CH₂Cl₂-system. The thioester isothiocyanates (R-3 andR-9) were oxidized to the corresponding sulfone analogs (R-4 and R-10)with good yields (55-60%) using m-chloroperbenzoic acid inCH₂Cl₂-solution according to Tucker et al., “Nonsteroidal Antiandrogens.Synthesis and Structure-Activity Relationships of 3-SubstitutedDerivatives of 2-Hydroxypropionanilides,” J. Med. Chem., 31(5)954-959(1988).

[0097] Azide R-5 was synthesized through diazotization of thecorresponding aniline R-1 followed by displacement of the diazonium saltwith sodium azide. The yield of the reaction was 77%.

[0098] Chloroacetamides (R-6 and R-11) (yield 75-80%) andbromoacetamides R-7 and R-12) (yield about 95%) (Scheme 3) were obtainedaccording to Tindall's procedure for synthesis of DHT-BA, describedChang et al., “Affinity Labeling of the Androgen Receptor in the RatProstate Cytosol with 17β -[(Bromoacetyl)oxy]-5α-androstan-3-one,Biochemistry, 23:2527-2533 (1984). The use of sterically hinderedN,N-diisopropylethylamine instead of triethylamine as the base avoidedthe undesirable reaction of bromoacetamide with the amine and gaveexcellent yields for these reactions. Oxidation of R-7 bym-chloroperbenzoic acid in CH₂Cl₂-solution according to Tucker et al.,“Nonsteroidal Antiandrogens. Synthesis and Structure-ActivityRelationships of 3-Substituted Derivatives of 2-Hydroxypropionanilides,”J. Med. Chem., 31(5)954-959 (1988) gave R-8 with excellent yield (82%).

Example 2

[0099] Receptor binding studies for the compounds shown in Table 3 wereconducted as follows.

[0100] Mibolerone (MIB) is a synthetic androgen with high affinity andhigh specificity for the AR.

[0101] Competitive displacement of ³H-MIB from AR binding sites by ourcompound was assessed as follows:

[0102] 1. AR were isolated from rat ventral prostate tissue bydifferential centrifugation.

[0103] 2. Samples of the following composition listed in Table 4 wereincubated at 4° C. for 18 hours: TABLE 4 ³H-MIB 1 nM Triamcinolone 1 μMTRIS buffer 10 mM AR protein 14.5 mg protein/ml, final concentrationCasodex analog 10⁻⁶ μM to 10 μM

[0104] Non-specific binding was determined by including MIB (1 μM) inthe above incubate.

[0105] 3. Bound ³H-MIB was separated by addition of a slurry ofhydroxyapatite, and extracted from hydroxyapatite with ethanol.

[0106] 4. Bound ³H-MIB was counted using liquid scintillationspectrometry.

Data Analysis

[0107] Percent Specific Binding=(B/B₀)×100

[0108] B=specific binding of ³H-MIB in the presence of a particularconcentration of compound of interest

[0109] B₀=specific binding of ³H-MIB in the absence of the compound

[0110] Data were computer fitted to the equation:

[0111]${{Specific}\quad {Binding}} = {B_{o}\left( {1 - \frac{C}{{1C_{50}} + C}} \right)}$

[0112]

[0113] C=isomer concentration

[0114] IC₅₀=isomer concentration that reduces % specific binding by 50%.

[0115] Equilibrium dissociation constant of each isomer (K_(i)) wasdetermined using the equation.

[0116] $K_{1} = \frac{1C_{50}K_{d}}{L + K_{d}}$

[0117]

[0118] K_(d)=equil. dissociation constant of ³H-MIB

[0119] L=concentration of ³H-MIB

[0120] The results are shown in Table 3 above.

[0121] AR binding studies of the compounds listed in Table 3 showed thatin all cases (R)-isomers had a higher AR binding affinity than(S)-isomers. This data is in agreement with the results found withCasodex enantiomers, Mukherjee et al., “Enantioselective Binding ofCasodex to the Androgen Receptor,” Xenobiotica, 22:117-22 (1996),((R-isomers>>(S)-isomers).

[0122] Oxidation of thioester compounds to sulfoxide derivatives (R-3 toR-4, R-7 to R-8, R-9 to R-10) enhanced the binding ability of thecompounds.

[0123] Comparison of the binding properties of the para- and themeta-substituted antiandrogens showed that substitution in thepara-position gives better binding compounds. The most exciting exampleof this effect on substitution is compounds R-6 and R-11. Shifting thechloroacetamide substituent from the meta-to the para-position causes adramatic (about three order of magnitude) increase in the K_(i)-value.Compounds R-4 and R-10, S-1 and S-2 show a less distinct effect. Thereis no difference in binding of compounds R-3 and R-9. However, compoundsR-1 and R-2, S-3 and S-9 show the opposite dependence with the bestbinding ocuring with the meta-analog.

[0124] Variation of binding affinity in the series of para- andmeta-substituted analogs is given below:

[0125] Para-substituted: Chloroacetamide R-6>azide R-5>amine R-1>bromoacetamide

R-7≈isothiocyanate R-3.

[0126] Meta-substituted: amine R-2>bromoacetamide R-12≈isothiocyanateR-9> chloroacetamide R-11.

[0127] Amino compounds bind to the AR better than bromoacetamides andisothiocyanates (R-1>R-7≈R-3, R-2>R-12≈R-9) which have fairly closeK_(i) values. The chloroacetamide analog has the highest binding in thepara-position (R-6) and binds very poorly to the AR in the meta-position(R-11).

[0128] Compound R-6 was found to have the highest binding to the AR ofany compounds.

Example 3

[0129] A series of electrophilic nonsteroidal compounds were designedand synthesized with the ability to irreversibly and permanently bindthe AR, and thereby permanently inhibit the ability of testosterone(“T”) and dihydrotestosterone (“DHT”) to bind the androgen receptor. Theability of these compounds was evaluated to: (A) compete for binding tothe AR, and (B) to irreversibly bind the AR and permanently inhibitbinding by other agents. The experimental methods and results of thesestudies are summarized below.

[0130] A. Abilty Of Our Compounds To Compete For AR Binding

[0131] Methods:

[0132] The ability of the compounds was evaluated to compete withmibolerone (MIB) for rat ventral prostate AR. MIB is a highly specificAR ligand which demonstrates greater affinity and specificity for the ARthan DHT, is not metabolized like T and DHT, and is not light-sensitiveas is the case for methyltrienolone (R1881), another commonly used ARradioligand. AR isolation was performed as follows. Bilateralorchiectomy was performed on male, Sprague-Dawley rats using sterilesurgical procedures. Animals were allowed 24 hr for recovery and thenwere anesthetized a second time for tissue procurement. Ventralprostates were removed, weighed, and immediately immersed in an ice-coldsolution of phosphate buffered saline. Ventral prostates were minced,homogenized, diluted in buffer, and then the tissue slurry wascentrifuged at 105,000 g for 1 h at 0° C. The supernatant (cytosol)fraction containing the AR was decanted, stored at −80° C., and used asthe AR source for binding studies. Our homogenization buffer consistedof 1.5 mM Na₂EDTA, 0.5 mM dithiothreitol, 0.25 M sucrose, 10 mM Na₂MoO₄,1 mM phenylmethyl sulfonyl fluoride (“PMSF”) in 10 mM TRIS, pH 7.4.Using this buffer, we isolated rat prostate AR and demonstrated that³H-MIB binding in the preparation is comprised of about 90% specificbinding to the AR and less than 10% to nonspecific binding sites. Thefirst step was to determine the equilibrium dissociation constant(“K_(d)”) of ³H-MIB in our AR preparation. Increasing concentrations of³H-MIB (10⁻¹¹ to 10⁻⁸ M) were incubated with AR at 4° C. for 18 hr, andthen bound and unbound ³H-MIB separated using hydroxylapatite (“HAP”).Data were analyzed using a modified form of the Scatchard equation (i.e.B/F=(−1/K_(d))B+ B_(max)/K_(d), where B is the concentration ofradioligand (³H-MIB) in the incubate present as ligand-AR complex, F isthe concentration of free ³H-MIB present in the incubate, and B_(max) isthe maximum concentration of radioligand which can be bound in theincubate. A plot of (AR-bound ³H-MIB/free ³H-MIB) versus (AR-bound³H-MIB) was constructed. The negative inverse of the slope of this plotyielded the value of K_(d) for MIB, 0.182 nM, in the AR preparation. Therelative binding affinity of each newly synthesized compound was thendetermined. Increasing concentrations (10⁻¹² to 10⁻⁵ M) of each compoundwere incubated with AR and a known concentration of ³H-MIB (1.0 nM).Data were plotted in terms of the specific binding (mean±S.D., n=3)expressed as a percent of control value (i.e., in the absence ofcompetitor) on the ordinate versus the logarithm of the concentration ofthe competitor. The concentration of competitor required to inhibitspecific binding by 50% (IC₅₀) was determined by computer-fitting theexperimental data to the Hill equation (NLIN procedure, SAS, SASInstitute, Cary, N.C.). The K_(i) for each compound was calculated bythe following equation: K_(i)=IC₅₀/(1+[L]/K_(d)), where IC₅₀ is theconcentration of competitor which inhibits the binding of ³H-MIB by 50%,[L] is the concentration of ³H-MIB added (1.0 nM), and K_(d) is theequilibrium dissociation constant for MIB (0.182 nM). The K_(i) of thetwo endogenous compounds (i.e., T and DHT) were also determined.

[0133] Results

[0134] A number of affinity labeled ligands and precursors weresynthesized, including S-nitro-thio-aniline (“S-NTA”),S-nitro-thio-isothiocyanate (“S-NT-NCS”), S-nitro-thio chloroacetamide(“S-NT-CAA”), and R- and S-Bromo-CyanoAnilide (“R-CAD” and “S-CAD”,respectively). These analogs were selected for early synthesis todemonstrate that the organic chemistry with various affinity labels andprecursors could be carried out. The chemical structures of theseanalogs and their AR binding affinities in rat prostate AR are shown inFIG. 1. AR binding affinities are reported in graphical form as logK_(i) values. Smaller K_(i) values indicate greater AR binding affinity.R-isomers are presented as solid bars in the FIGS. 1 and 2; S-isomers asdotted bars, and racemic mixtures as bars with diagonal lines.

[0135] Several previously synthesized compounds (i.e., Casodex andThio-Casodex) are included for the sake of comparison. It is importantto note that the AR binding affinities of the ligands (i.e., S-NTA,S-NT-NCS, and S-NT-CAA) are close to that of S-Casodex, demonstratingthat the incorporation of these functional groups into the compound didnot significantly interfere with AR binding ability. The K_(i) value forT (1.09±0.2 nM, not pictured) was in agreement with values previouslypublished by other investigators, indicating the validity of ourresults.

[0136] Synthesis was completed of several R-isomers of potentialirrversible AR ligands, including four isothiocyanate (“NCS”), threebromoacetamide (“BAA”), and two chloroacetamide (“CAA”) derivatives.Structures and Ki values for these para (p) and meta (m)-substitutedderivatives are presented in FIG. 2. In all cases, Casodex derivatives(sulfones, denoted as S in FIG. 2) showed greater binding affinities(i.e., lower K_(i) values) than their corresponding un-oxidizedthioprecursors (denoted as T in the figure): p-S-NCS>p-T-NCS, m-S-NCS>mT-NCS, and p-S-BAA>p-T-BAA. Of the isothiocyanate derivatives, theR-cyanotrifluoro sulfo-p-isothiocyanate derivative (p-S-NCS) bound withgreatest affinity (K_(i)=31 nM). The remaining isothiocyanates and theacetamides (bromo and chloro), with one notable exception, demonstratedweaker interactions with the AR (i.e., K_(i) values close to orconsiderably greater than 100 nM). TheR-cyano-trifluoro-thio-p-chloroacetamide derivative (p-T-CAA) bound theAR with extremely high affinity (K_(i,)3 D=1.6 nM). These resultsdemonstrate that we are able to develop a wide variety of potentialirrversible compounds, and maintain binding affinities near the range ofbinding affinities of known antagonists for the AR. Thus, theaforementioned compounds (i.e., bromoacetamides, chloroacetamides, andisothiocyanates) were carried forward to studies to examine theirirreversibility.

[0137] B. Ability Of Our Compounds To Irreversibly Bind The AR

[0138] Methods:

[0139] The proposed agents were designed to irreversibly bind the AR.The ability of the compounds to do so was examined using an AR exchangeassay. Rat ventral prostate AR was prepared as previously described andused as the receptor source. AR was pre-incubated with reversible orpotentially irreversible ligands (10 μM final concentration) in separateexperiments at 4° C. for up to 12 hours. Control experiments with noligand were performed to account for decreases in binding due to ARdegradation. Hydroxylapatite (“HAP”) was added to the ligand-cytosolmixture and allowed to incubate for an additional 15 min. The HAP-ARcomplex was centrifuged and then resuspended in ice cold homogenizationbuffer. This procedure was repeated twice to ensure complete removal ofreversibly bound ligands. The HAP-AR complex was resuspended a finaltime in buffer containing 1 nM ³H-MIB. Separate tubes containing 5 μMunlabeled MIB were used in all experiments to determine the extent ofnon-specific binding. Incubations were maintained at 4° C. for anadditional 12 hr, and then specifically AR-bound ³H-MIB determined asdescribed above. Reversible ligands will dissociate from the AR duringwashing, and thus demonstrate near 100% recovery of exchangeablespecific ³H-MIB binding sites as compared to controls. Irreversible ARbinding by a ligand will appear as a significant decrease inexchangeable ³H-MIB binding sites. R-Casodex, a known reversibleantiandrogen, and two reversible aniline derivatives synthesized in ourlaboratories (T-aniline and m-T-aniline) were included in the studies todemonstrate the validity of the experimental system.

[0140] Results

[0141] AR exchange assays were performed in order to assess the level ofirreversible binding that was occurring with the compounds. The resultsare presented in FIG. 3. R-Casodex, R-CyanoTrifluoro-Thio-p-aniline(“p-T-aniline”) and R-CyanoTrifluoro-Thio-m-aniline (“m-T-aniline”) donot contain electrophilic groups and are, thus, incapable ofirreversible binding to the AR.

[0142] As expected, exchangeable specific binding for these compounds(as a % of control) was near 100%. None of the bromoacetamide (“BAA”)derivatives tested caused a decrease in exchangeable specific binding of³H-MIB. However, the para-substituted isothiocyanate (“p-T NCS” and“p-S-NCS”) and chloroacetamide (“p-T-CAA”) derivatives significantlydecreased exchangeable specific binding by ³H-MIB. Thepara-isothiocyanate derivatives of thio Casodex and Casodex (“p-T-NCS”and “p-S-NCS”, respectively in the FIG. 3) decreased exchangeablebinding to 16 and 15% of control, respectively. Likewise, theparachloroacetamide derivative of thio-Casodex (“p-T-CAA”) decreasedexchangeable specific binding to 25% of control values. These compounds,therefore, represent the first irreversibly binding compounds for theAR. With the exception of the meta-isothiocyanate derivative of Casodex(“m-S-NCS”), the meta-substituted derivatives of these same compoundsshowed no such ability for irreversible binding to the AR, suggestingthat the para-substituted affinity ligands more favorably interact witha nucleophile in the ligand binding domain of the AR.

[0143] As a final point, it is important to note that the ability toirreversibly bind the AR was not directly related to the AR bindingaffinity. The p-isothiocyanate derivative of Thio-Casodex (“p-T-NCS”)showed weaker binding affinity (i.e., K_(i)= 390 nM), but was able todecrease exchangeable binding to the same extent as its correspondingsulfone derivative (“p-S-NCS”, K_(i)=31 nM), supporting the contentionthat para-substituted isothiocyanate derivatives selectively seek outnucleophiles in the AR ligand binding domain. We also completed apreliminary experiment to examine time-dependent AR inactivation by thepara-isothiocyanate derivative of Casodex (“p S-NCS”, open circles) ascompared to the reversible parent compound Casodex (closed circles)(FIG. 4). A lower concentration of the individual ligands (2 μM) wasincubated for various periods of time before treatment with HAP, andsubsequent exchange with 1 nM ³H-MIB. p-S NCS rapidly (i.e., within 0.5hr) decreased the number of exchangeable AR binding sites to 50% of thatobserved in control incubations with no ligand. Exchangeable specificbinding for Casodex was near 100% of control at all time points. Insummary, these studies indicate that three of the compounds (i.e.,p-T-NCS, p-S-NCS, and p-T-CAA) bind the AR irreversibly.

[0144] Although the invention has been described in detail for thepurpose of illustration, it is understood that such detail is solely forthat purpose, and variations can be made therein by those skilled in theart without departing from the spirit and scope of the invention whichis defined by the following claims.

What is claimed:
 1. A method for treating prostate cancer in a patientcomprising: administering to the patient an effective amount of acompound, wherein the compound binds irreversibly to the androgenreceptor of the patient.
 2. The method according to claim 1 , where thecompound has the formula:

wherein R₁, R₂ and R₃, are the same or different and are a hydrogen, anitro, a cyano, a carbamoyl, a halogen, a perfluoroalkyl, ahaloalkylamido, an isothiocyanate, an azide, a diazocarbonyl, asubstituted oxirane, or a β-chloroethylamine; R₄ is a hydrogen, analkyl, or is joined to R₅; R₅ is a hydrogen, a hydroxy, an alkoxy, anacyloxy, an amino, an alkylamino, a halogen, or is joined to R₄; R₆ is ahydrogen, an alkyl, or a halogenoalkyl; A₁ and A₂ is the same ordifferent, each is direct link or alkylene; X₁ is a halogen, an oxygen,a sulfur, a sulphinyl, a sulphonyl, an amino, an alkylimino, or analkylene; and R₇ is a hydrogen, a halogen, an alkoxy, a haloalkoxy, anacyloxy, a haloacyloxy, an aryloxy, a thioalkyl, a thioraryl, asulphinyl, a haloalkyl sulphinyl, a sulphonyl, a haloalkylsulphonyl, anamino, an alkylimino, an alkylamido group, a haloalkylamido group, anisothiocyanate, an azide, a diazocarbonyl, a substituted oxirane, aβ-chloroethylamine, or a phenyl optionally substituted with a halogen, anitro group, an alkyl, a haloalkyl, a cyano, a hydroxyl, a carboxylicgroup, an amino, an alkylamino, an alkylamido group, a haloalkylamidogroup, an isothiocyanate, an azide, a diazocarbonyl, a substitutedoxirane, or a β-chloroethylamine.
 3. A method for treating prostatecancer in a patient comprising: administering to the patient aneffective amount of a compound having the formula:

where Z is NCS or CN; R is F, NH₂, NCS, N₃ or NHCOCH₂Y; X is S or SO₂;and Y is a halogen; wherein the compound binds irreversibly to anandrogen receptor of the patient.
 4. The method according to claim 3 ,wherein Z is CN, X is S, and R is NHCOCH₂Cl.
 5. The method according toclaim 3 , wherein Z is CN, X is S, and R is NCS.
 6. The method accordingto claim 3 , wherein Z is CN, X is SO₂, and R is NCS.
 7. The methodaccording to claim 3 , wherein Z is NCS, X is SO₂, and R is F.
 8. Acompound which binds irreversibly to the androgen receptor of a patient.9. The compound according to claim 8 , wherein the compound has theformula:

wherein R₁, R₂ and R₃, are the same or different and are a hydrogen, anitro, a cyano, a carbamoyl, a halogen, a perfluoroalkyl, ahaloalkylamido, an isothiocyanate, an azide, a diazocarbonyl, asubstituted oxirane, or a β-chloroethylamine; R₄ is a hydrogen, analkyl, or is joined to R₅; R₅ is a hydrogen, a hydroxy, an alkoxy, anacyloxy, an amino, an alkylamino, a halogen, or is joined to R₄; R₆ is ahydrogen, an alkyl, or a halogenoalkyl; A₁ and A₂ is the same ordifferent, each is direct link or alkylene; X₁ is a halogen, an oxygen,a sulfur, a sulphinyl, a sulphonyl, an amino, an alkylimino, or analkylene; and R₇ is a hydrogen, a halogen, an alkoxy, a haloalkoxy, anacyloxy, a haloacyloxy, an aryloxy, a thioalkyl, a thioraryl, asulphinyl, a haloalkyl sulphinyl, a sulphonyl, a haloalkylsulphonyl, anamino, an alkylimino, an alkylamido group, a haloalkylamido group, anisothiocyanate, an azide, a diazocarbonyl, a substituted oxirane, aβ-chloroethylamine, or a phenyl optionally substituted with a halogen, anitro group, an alkyl, a haloalkyl, a cyano, a hydroxyl, a carboxylicgroup, an amino, an alkylamino, an alkylamido group, a haloalkylamidogroup, an isothiocyanate, an azide, a diazocarbonyl, a substitutedoxirane, or a β-chloroethylamine.
 10. A compound having the formula:

where Z is NCS or CN; R is F, NH₂, NCS, N₃ or NHCOCH₂Y; X is S or SO₂;and Y is a halogen.
 11. The compound according to claim 10 , wherein Zis CN, X is S, and R is NHCOCH₂Cl.
 12. The compound according to claim10 , wherein Z is CN, X is S, and R is NCS.
 13. The compound accordingto claim 10 , wherein Z is CN, X is SO₂, and R is NCS.
 14. The compoundaccording to claim 10 , wherein Z is NCS, X is SO₂, and R is F.
 15. Thecompound according to claim 10 , wherein the compound binds irreversiblyto an androgen receptor of a mammal.
 16. A pharmaceutical compositioncomprising: a compound having the formula:

wherein R₁, R₂ and R₃, are the same or different and are a hydrogen, anitro, a cyano, a carbamoyl, a halogen, a perfluoroalkyl, ahaloalkylamido, an isothiocyanate, an azide, a diazocarbonyl, asubstituted oxirane, or a β-chloroethylamine; R₄ is a hydrogen, analkyl, or is joined to R₅; R₅ is a hydrogen, a hydroxy, an alkoxy, anacyloxy, an amino, an alkylamino, a halogen, or is joined to R₄; R₆ is ahydrogen, an alkyl, or a halogenoalkyl; A₁ and A₂ is the same ordifferent, each is direct link or alkylene; X₁ is a halogen, an oxygen,a sulfur, a sulphinyl, a sulphonyl, an amino, an alkylimino, or analkylene; and R₇ is a hydrogen, a halogen, an alkoxy, a haloalkoxy, anacyloxy, a haloacyloxy, an aryloxy, a thioalkyl, a thioraryl, asulphinyl, a haloalkyl sulphinyl, a sulphonyl, a haloalkylsulphonyl, anamino, an alkylimino, an alkylamido group, a haloalkylamido group, anisothiocyanate, an azide, a diazocarbonyl, a substituted oxirane, aβ-chloroethylamine, or a phenyl optionally substituted with a halogen, anitro group, an alkyl, a haloalkyl, a cyano, a hydroxyl, a carboxylicgroup, an amino, an alkylamino, an alkylamido group, a haloalkylamidogroup, an isothiocyanate, an azide, a diazocarbonyl, a substitutedoxirane, or a β-chloroethylamine; and a pharmaceutically acceptablecarrier.
 17. The composition according to claim 16 , wherein thecompound has the formula:

where Z is NCS or CN; R is F, NH₂, NCS, N₃ or NHCOCH₂Y; X is S or SO₂;and Y is a halogen;
 18. The composition according to claim 17 , whereinZ is CN, X is S, and R is NHCOCH₂Cl.
 19. The composition according toclaim 17 , wherein Z is CN, X is S, and R is NCS.
 20. The compositionaccording to claim 17 , wherein Z is CN, X is SO₂, and R is NCS.
 21. Thecomposition according to claim 17 , wherein Z is NCS, X is SO₂, and R isF.
 22. The composition according to claim 16 , wherein the compositionbinds irreversibly to an androgen receptor of a mammal.
 23. Thecomposition according to claim 17 , wherein the composition bindsirreversibly to an androgen receptor of a mammal.